The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

• Published in: Oncogene 2016-01, Vol.35 (4), p.415-426
• Main Authors: Bailly, A, Perrin, A, Bou Malhab, L J, Pion, E, Larance, M, Nagala, M, Smith, P, O'Donohue, M-F, Gleizes, P-E, Zomerdijk, J, Lamond, A I, Xirodimas, D P
• Format: Article
• Language: English
• Subjects: 631/337; 82; 82/58; 96/106; Animals; Apoptosis; Biochemistry, Molecular Biology; Caenorhabditis elegans; Caenorhabditis elegans - cytology; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins; Cancer; Cancer therapies; Cell Biology; Cell Line - drug effects; Cell Nucleolus - drug effects; Cellular Biology; Cyclopentanes - pharmacology; Genes, p53 - drug effects; Genetic transcription; Health aspects; Human Genetics; Humans; Innovations; Internal Medicine; Life Sciences; MCF-7 Cells - drug effects; Medicine; Medicine & Public Health; Metabolic Networks and Pathways - drug effects; Metabolic Networks and Pathways - genetics; Mice, Mutant Strains; Molecular targeted therapy; NEDD8 Protein; Oncology; original-article; Properties; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Pyrimidines - pharmacology; Ribonucleic acid; Ribosomal Proteins - genetics; Ribosomal Proteins - metabolism; Ribosomal RNA; Ribosomes - drug effects; Ribosomes - genetics; Ribosomes - metabolism; RNA; Studies; Tumor proteins; Ubiquitins - antagonists & inhibitors; Ubiquitins - genetics; Ubiquitins - metabolism
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.104

The ubiquitin-like molecule NEDD8 is essential for viability, growth and development, and is a potential target for therapeutic intervention. We found that the small molecule inhibitor of NEDDylation, MLN4924, alters the morphology and increases the surface size of the nucleolus in human and germline cells of Caenorhabditis elegans in the absence of nucleolar fragmentation. SILAC proteomics and monitoring of rRNA production, processing and ribosome profiling shows that MLN4924 changes the composition of the nucleolar proteome but does not inhibit RNA Pol I transcription. Further analysis demonstrates that MLN4924 activates the p53 tumour suppressor through the RPL11/RPL5-Mdm2 pathway, with characteristics of nucleolar stress. The study identifies the nucleolus as a target of inhibitors of NEDDylation and provides a mechanism for p53 activation upon NEDD8 inhibition. It also indicates that targeting the nucleolar proteome without affecting nucleolar transcription initiates the required signalling events for the control of cell cycle regulators.